期刊
HUMAN GENE THERAPY
卷 31, 期 19-20, 页码 1114-1123出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2020.099
关键词
recombinant adeno-associated virus serotype 3 vector; gene therapy; hemophilia B
资金
- Public Health Service [R01 HL-097088, R41 AI122735, R21 EB-015684]
- Children's Miracle Network
- Kitzman Foundation [BT/PR17316/MED/31/326/2015]
- Department of Biotechnology, Government of India
Although recombinant adeno-associated virus serotype 8 (AAV8) and serotype 5 (AAV5) vectors have shown efficacy in Phase 1 clinical trials for gene therapy of hemophilia B, it has become increasingly clear that these serotypes are not optimal for transducing primary human hepatocytes. We have previously reported that among the 10 most commonly used AAV serotypes, AAV serotype 3 (AAV3) vectors are the most efficient in transducing primary human hepatocytesin vitroas well as in humanized micein vivo, and suggested that AAV3 vectors expressing human coagulation factor IX (hFIX) may be a more efficient alternative for clinical gene therapy of hemophilia B. In the present study, we extended these findings to develop an AAV3 vector incorporating a compact yet powerful liver-directed promoter as well as optimized hFIX cDNA sequence inserted between two AAV3 inverted terminal repeats. When packaged into an AAV3 capsid, this vector yields therapeutic levels of hFIX in hemophilia B and in humanized micein vivo.Together, these studies have resulted in an AAV3 vector predicted to achieve clinical efficacy at reduced vector doses, without the need for immune-suppression, for clinical gene therapy of hemophilia B.
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